1. Field of the Invention
The invention relates to the treatment of cancer, and in particular embodiments to cancers of the central nervous system (“CNS”), such as those found in the brain.
2. Description of Related Art
Malignant brain tumors are among the gravest forms of cancer. The most common of these incurable tumors, glioblastoma multiforme (“GBM”), is responsible for 50% of all intracranial gliomas and 25% of intracranial tumors in adults. See, e.g., L. M. DeAngelis, “Medical progress: Brain tumors,” N. Engl. J. Med., 344:114 (2001); and F. G. Davis et al., “Prevalence estimates for primary brain tumors in the United States by behavior and major histology groups,” Neuro-oncol. 3:152 (2001). GBM diagnosis carries with it an average survival between twelve and eighteen months (with 90-95% patients surviving less than two years), without the possibility of spontaneous remission or effective treatment. See, e.g. Id.; and W. J. J. Curran et al., “Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials,” J. Natl. Cancer Inst., 85:690 (1993). The consistently short survival and absence of spontaneous remission that makes GBM such a devastating disease also renders the evaluation of new therapies for this disease relatively rapid and unequivocal. Overall survival represents the standard by which therapies for GBM are evaluated, in part because tumor mass reduction (i.e., surgically) does not necessarily correlate with prolonged survival. See, e.g., F. W. Kreth et a., “Surgical resection and radiation therapy versus biopsy and radiation therapy in the treatment of glioblastoma multiforme,” J. Neurosurg., 78:762 (1993); M. R. Quigley et al., “Value of surgical intervention in the treatment of glioma,” Stereotact. Funct. Neurosurg., 65:171 (1995); and S. J. Hentschel et al., “Current surgical management of glioblastoma,” Cancer J., 9:113 (2003).
Unfortunately, conventional therapies are remarkably ineffective at improving GBM clinical outcome, despite their ability to confer significant benefits to patients with non-glioma tumors. See, e.g., Curran at 690; J. F. Reavey-Cantwell et al., “The prognostic value of tumor markers in patients with glioblastoma multiforme: analysis of 32 patients and review of the literature,” J. Neurooncol., 55:195 (2001); and R. Stupp et al., “Recent developments in the management of malignant glioma,” J. Clin. Oncol., 1091-9118:779 (2001). Even the few treatments effective against GBM typically either exhibit small increases in survival that are evident only from large population studies, or primarily benefit certain (i.e., young) patient subpopulations. See, e.g., H. A. Fine et al., “Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults,” Cancer, 71:2585 (1993); and S. Diete et al., “Sex differences in length of survival with malignant astrocytoma, but not with glioblastoma,” J. Neurooncol., 53:47 (2001). Thus, there exists a need in the art for a novel therapy for GBM.
Cancer vaccines represent one such therapy for GBM. See, e.g. R. P. Glick et al., “Intracerebral versus subcutaneous immunization with allogeneic fibroblasts genetically engineered to secrete interleukin-2 in the treatment of central nervous system glioma and melanoma,” Neurosurg., 41:898 (1997); L. M. Liau et al., “Treatment of intracranial gliomas with bone marrow-derived dendritic cells pulsed with tumor antigens,” J. Neurosurg., 90:1115 (1999); and J. S. Yu et al., “vaccination of malignant glioma patients with peptide-pulsed DC elicits systemic cytotoxicity and intracranial T-cell infiltration,” Cancer Res., 61:842 (2001). The clinical efficacy of therapeutic vaccination for any human tumor, however, remains controversial because consistent tumor destruction or extended lifespan is not observed in most vaccinated cancer patients. See, e.g., S. A. Rosenberg et al., “Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma,” Nat. Med., 4:321 (1998); K. H. Lee et al., “Increased vaccine-specific T cell frequency after peptide based vaccination correlates with increased susceptibility to in vitro stimulation but does not lead to tumor regression,” J. Immunol., 163:6292 (1999); and L. Fong et al., “Altered peptide ligand vaccination with Flt3 ligand expanded DC for tumor immunotherapy,” Proc. Natl. Acad. Sci. USA, 98:8809 (2001). In contrast, current cancer vaccines do reliably elicit tumor-reactive cytotoxic T lymphocytes (“CTL”) in most patients. See, e.g., Rosenberg at 321; Lee at 6292; and B. Bodey et al., “Failure of cancer vaccines: the significant limitations of this approach to immunotherapy,” Anticancer Res., 20:2665 (2000). The reasons underlying the general clinical failure of cancer vaccines are unknown, but one possibility is that the kinetics of anti-tumor CTL killing in cancer patients may be too inefficient to keep pace with rapidly growing, mutating tumors in situ. Consistent with this notion, it was previously reported that therapeutic vaccination with autologous tumor antigen-pulsed DC is sufficient to enhance peripheral tumor-reactive CTL activity and CD8+ T cell infiltration into tumors in situ in GBM patients. See Yu et al. at 842. Nevertheless, improvements in overall patient survival were not apparent in this initial study.
Because CTL induce death in their cellular targets, it is not unreasonable to expect that inefficient CTL killing might either incompletely trigger death pathways in targeted tumor cells, or select for CTL-resistant tumor variants. In the first case, vaccine-elicited tumor-responsive CTL might fundamentally alter tumors by “priming” their death machinery. In the second case, such CTL could fundamentally alter tumor cell physiology and/or genetics. Both of these possibilities could, in theory, be exploited by additional therapeutic modalities. Therefore, the clinical insufficiency of cancer vaccines encourages the examination of synergy between vaccination and other therapies, particularly to the extent that such an examination might uncover a novel approach to cancer therapy.